We will extend our investigations of the ileal and renal bile salt transport systems. These two systems function in the entero-hepatic circulation of bile salts and their biological economy, and were first described by this laboratory. The studies will include the following: a. the isolation and purification of macromolecules functioning in ileal transport from brush border membranes will be initiated. Evidence for assessing their transport function will be an assay system using reconstituted mixed liposome vesicles. b. Our structure-activity studies have yielded information on the topography at the active site and has allowed us to design in a predicting manner, modified bile salt derivatives which can act as refractory substrates with inhibitory properties. We will continue these investigations to develop more effective reversible and irrevesible inhibitors. The pharmacology of these inhibitors will then be assessed. We will continue our studies on the intra-hepatic events that are involved in the biological control of the catabolism of cholesterol to bile salts. Using hepatocyte preparations we will delineate the role that bile salts (which are in themselves steroids) might have as moderators of the effectiveness of steroid hormones as inducers of cholesterol 7gamma-hydroxylase, the rate limiting enzyme operating in the catabolic conversion of cholesterol to bile salts. b. Structure-activity studies of this type of hormone inducer will be carried out to ascertain if a theoretical model can be made.